Taurocholate Induces Biliary Differentiation of Liver Progenitor Cells Causing Hepatic Stellate Cell Chemotaxis in the Ductular Reaction

Pozniak, Katarzyna N.; Pearen, Michael A.; Pereira, Tamara N.; Croft, Priyakshi Kalita-de; Nawaratna, Sujeevi; Gobert, Geoffrey N.; Tirnitz–Parker, Janina E.E.; Olynyk, John K.; Shepherd, Ross W.; Lewindon, Peter; Ramm, Grant A.

doi:10.1016/j.ajpath.2017.08.024

Cited by 21 publications

(21 citation statements)

References 46 publications

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“…Moreover, a significant increase of miR‐34a expression has been reported in liver disease, including cholestasis . Based on our previous studies, we have proposed a role for the hydrophobic bile acid, taurocholate, in the abnormal development of bile ducts, a process known as the ductular reaction, in CFLD . Key components of the Notch signaling pathway, such as Notch1, Notch2, and Jagged1, are direct targets of miR‐34a .…”

Section: Discussionmentioning

confidence: 98%

“…(39) Based on our previous studies, (40) we have proposed a role for the hydrophobic bile acid, taurocholate, in the abnormal development of bile ducts, a process known as the ductular reaction, in CFLD. (41) Key components of the Notch signaling pathway, such as Notch1, Notch2, and Jagged1, are direct targets of miR-34a. (42) There is supporting evidence that hepatic stellate cells (HSCs) and macrophages can influence the differentiation of liver progenitor cells into reactive biliary cells and bile ducts by the Notch pathway, (43) therefore suggesting a potential role of miR-34a in the manifestation of CFLD.…”

Section: Discussionmentioning

confidence: 99%

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MicroRNA Sequencing Identifies a Serum MicroRNA Panel, Which Combined With Aspartate Aminotransferase to Platelet Ratio Index Can Detect and Monitor Liver Disease in Pediatric Cystic Fibrosis

et al. 2018

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Cystic fibrosis (CF)-associated liver disease (CFLD) is a hepatobiliary complication of CF. Current diagnostic modalities rely on nonspecific assessments, whereas liver biopsy is the gold standard to assess severity of fibrosis. MicroRNAs (miRNAs) regulate liver disease pathogenesis and are proposed as diagnostic biomarkers. We investigated the combined use of serum miRNAs and aspartate aminotransferase (AST) to platelet ratio (APRI) to diagnose and assess CFLD severity. This was a cross-sectional cohort study of the circulatory miRNA signature of 124 children grouped by clinical, biochemical, and imaging assessments as follows: CFLD (n = 44), CF patients with no evidence of liver disease (CFnoLD; n = 40), and healthy controls (n = 40). Serum miRNAs were analyzed using miRNA sequencing (miRNA-Seq). Selected differentially expressed serum miRNA candidates were further validated by qRT-PCR and statistical analysis performed to evaluate utility to predict CFLD and fibrosis severity validated by liver biopsy, alone or in combination with APRI. Serum miR-122-5p, miR-365a-3p, and miR-34a-5p levels were elevated in CFLD compared to CFnoLD, whereas miR-142-3p and let-7g-5p were down-regulated in CFLD compared to CFnoLD. Logistic regression analysis combining miR-365a-3p, miR-142-3p, and let-7g-5p with APRI showed 21 times greater odds of accurately predicting liver disease in CF with an area under the receiver operating characteristics curve (AUROC) = 0.91 (sensitivity = 83%, specificity = 92%; P < 0.0001). Expression levels of serum miR-18a-5p were correlated with increasing hepatic fibrosis (HF) stage in CFLD (r = 0.56; P < 0.0001), showing good diagnostic accuracy for distinguishing severe (F3-F4) from mild/moderate fibrosis (F0-F2). A unit increase of miR-18a-5p showed a 7-fold increased odds of having severe fibrosis with an AUROC = 0.82 (sensitivity = 93%, specificity = 73%; P = 0.004), indicating its potential to predict fibrosis severity. Conclusion: We identified a distinct circulatory miRNA profile in pediatric CFLD with potential to accurately discriminate liver disease and fibrosis severity in children with CF.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

MicroRNA Sequencing Identifies a Serum MicroRNA Panel, Which Combined With Aspartate Aminotransferase to Platelet Ratio Index Can Detect and Monitor Liver Disease in Pediatric Cystic Fibrosis

et al. 2018

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“…DR is a process that occurs hand in hand with HSC activation in a subset of liver diseases [28]. RDCs are able to secrete multiple soluble pro-fibrogenic factors acting on HSCs and myofibroblasts [37]. In this regard, work from our laboratory demonstrated the enrichment of α-SMA-positive cells in close proximity to LC3B-positive ductule structures (observed both in the livers of cirrhotic patients and in a rat model of AAF/CCL 4 -induced liver cirrhosis), providing evidence that autophagy may have a role in this paracrine interaction between RDCs and myofibroblasts.…”

Section: Reactive Ductular Cellsmentioning

confidence: 99%

Complex Cell Type-Specific Roles of Autophagy in Liver Fibrosis and Cirrhosis

et al. 2020

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The lysosomal degradation pathway, or autophagy, plays a fundamental role in cellular, tissue, and organismal homeostasis. A correlation between dysregulated autophagy and liver fibrosis (including end-stage disease, cirrhosis) is well-established. However, both the up and downregulation of autophagy have been implicated in fibrogenesis. For example, the inhibition of autophagy in hepatocytes and macrophages can enhance liver fibrosis, whereas autophagic activity in hepatic stellate cells and reactive ductular cells is permissive towards fibrogenesis. In this review, the contributions of specific cell types to liver fibrosis as well as the mechanisms underlying the effects of autophagy are summarized. In view of the functional effects of multiple cell types on the complex process of hepatic fibrogenesis, integrated approaches that consider the role of autophagy in each liver cell type should be a focus of future research.

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“…Moreover, the presence of hepatobiliary LPCs, marked by epithelial cell adhesion molecule (EpCAM) and cytokeratin 7 and 19, predicted an increased risk of tumour formation in cirrhotic, hepatitis C virus-infected patients (22). This suggests that some LPCs either indirectly influence tumour development by regulating the fibrogenic potential and chemotaxis of neighbouring hepatic stellate cells (9,12,13,23) or directly as tumour-initiating or cancer stem cells (CSCs).…”

Section: Liver Progenitor Cells and Cancer Stem Cellsmentioning

confidence: 99%

Wnt/?-Catenin Signalling during Liver Metabolism, Chronic Liver Disease and Hepatocarcinogenesis

Shirolkar¹,

Pasic²,

Gogoi-Tiwari³

et al. 2018

jrenhep

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Chronic liver diseases (CLDs) are increasing in prevalence and their end-stage complications, namely, cirrhosis, liver failure and hepatocellular carcinoma represent major global challenges. The most common initiators of progressive CLD are viral hepatitis and long-term alcohol abuse as well as steatosis and steatohepatitis. Irrespective of the underlying aetiology, a common feature of CLD is the formation of hepatic ductular reactions, involving the proliferation of liver progenitor cells (LPCs) and their signalling to fibrosis-driving hepatic stellate cells. The Wnt/β-catenin pathway has been found to regulate development, stemness and differentiation, and alterations in its activity have been associated with tumour development. Recent data highlight the role of Wnt/β-catenin signalling in hepatic metabolism, steatosis and cancer, and suggest targeting of this pathway as a promising molecular strategy to potentially inhibit CLD progression and hepatocarcinogenesis.

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Taurocholate Induces Biliary Differentiation of Liver Progenitor Cells Causing Hepatic Stellate Cell Chemotaxis in the Ductular Reaction

Cited by 21 publications

References 46 publications

MicroRNA Sequencing Identifies a Serum MicroRNA Panel, Which Combined With Aspartate Aminotransferase to Platelet Ratio Index Can Detect and Monitor Liver Disease in Pediatric Cystic Fibrosis

MicroRNA Sequencing Identifies a Serum MicroRNA Panel, Which Combined With Aspartate Aminotransferase to Platelet Ratio Index Can Detect and Monitor Liver Disease in Pediatric Cystic Fibrosis

Complex Cell Type-Specific Roles of Autophagy in Liver Fibrosis and Cirrhosis

Wnt/?-Catenin Signalling during Liver Metabolism, Chronic Liver Disease and Hepatocarcinogenesis

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